Effect of Cytochrome P450 2C19 and 2C9 Amino Acid Residues 72 and 241 on Metabolism of Tricyclic Antidepressant Drugs

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  • Attia Tamer Zekry
    Graduate School of Pharmaceutical Sciences, Osaka University Analytical Chemistry Department, Faculty of Pharmacy, Minia University
  • Yamashita Taku
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Hammad Mohamed Abdelkhalek
    Graduate School of Pharmaceutical Sciences, Osaka University Analytical Chemistry Department, Faculty of Pharmacy, Minia University
  • Hayasaki Akinori
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Sato Takumi
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Miyamoto Masayoshi
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Yasuhara Yuki
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Nakamura Takashi
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Kagawa Yusuke
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Tsujino Hirofumi
    Graduate School of Pharmaceutical Sciences, Osaka University
  • Omar Mahmoud Ahmed
    Analytical Chemistry Department, Faculty of Pharmacy, Minia University
  • Abdelmageed Osama Hassan
    Analytical Chemistry Department, Faculty of Pharmacy, Minia University Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University
  • Derayea Sayed Mohamed
    Analytical Chemistry Department, Faculty of Pharmacy, Minia University
  • Uno Tadayuki
    Graduate School of Pharmaceutical Sciences, Osaka University

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Abstract

Although cytochromes P450 2C9 (CYP2C9) and 2C19 (CYP2C19) have 91% amino acid identity, they have different substrate specificities. Previous studies have suggested that several amino acid residues may be involved in substrate specificity. In this study, we focused on the roles of two amino acids, residues 72 and 241. The amino acids in these positions have opposite charges in CYP2C9 and 2C19; the former has lysines in both positions (Lys72 and Lys241), and the latter has glutamic acids (Glu72 and Glu241). Reciprocal mutants for both CYP2C19 and 2C9 were produced, and their metabolic activities and spectroscopic properties were examined using three tricyclic antidepressant (TCA) drugs: amitriptyline, imipramine, and dothiepin. Although CYP2C19 wild-type (WT) had a high metabolic activity for all three drugs, the E72K mutation decreased enzymatic activity by 29–37%, while binding affinities were diminished 2.5- to 20-fold. On the other hand, low activity and low affinity of CYP2C9 WT were recovered notably by K72E mutation. The metabolic activities and binding affinities were minimally affected by CYP2C19 E241K and CYP2C9 K241E mutations. We could also show linear correlations between metabolic activities and binding affinities, and hence we conclude that amino acid residue 72 plays a key role in TCA drug metabolism by limiting the binding affinities of CYP2C19 and CYP2C9.

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